Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival

Marin E. Nelson, Sujoy Lahiri, Jenny D. Y. Chow, Frances L. Byrne, Stefan R. Hargett, David S. Breen, Ellen M. Olzomer, Lindsay E. Wu, Gregory J. Cooney, Nigel Turner, David E. James, Jill K. Slack-Davis, Carolin Lackner, Stephen H. Caldwell and Kyle L. Hoehn ()
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Marin E. Nelson: University of Virginia
Sujoy Lahiri: University of Virginia
Jenny D. Y. Chow: University of Virginia
Frances L. Byrne: University of Virginia
Stefan R. Hargett: University of Virginia
David S. Breen: University of Virginia
Ellen M. Olzomer: School of Biotechnology and Biomolecular Sciences, University of New South Wales
Lindsay E. Wu: School of Biotechnology and Biomolecular Sciences, University of New South Wales
Gregory J. Cooney: Charles Perkins Centre, The University of Sydney
Nigel Turner: School of Biotechnology and Biomolecular Sciences, University of New South Wales
David E. James: Charles Perkins Centre, The University of Sydney
Jill K. Slack-Davis: Immunology and Cancer Biology, University of Virginia
Carolin Lackner: Institute of Pathology, Medical University of Graz
Stephen H. Caldwell: University of Virginia
Kyle L. Hoehn: University of Virginia

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract The metabolic pathway of de novo lipogenesis is frequently upregulated in human liver tumours, and its upregulation is associated with poor prognosis. Blocking lipogenesis in cultured liver cancer cells is sufficient to decrease cell viability; however, it is not known whether blocking lipogenesis in vivo can prevent liver tumorigenesis. Herein, we inhibit hepatic lipogenesis in mice by liver-specific knockout of acetyl-CoA carboxylase (ACC) genes and treat the mice with the hepatocellular carcinogen diethylnitrosamine (DEN). Unexpectedly, mice lacking hepatic lipogenesis have a twofold increase in tumour incidence and multiplicity compared to controls. Metabolomics analysis of ACC-deficient liver identifies a marked increase in antioxidants including NADPH and reduced glutathione. Importantly, supplementing primary wild-type hepatocytes with glutathione precursors improves cell survival following DEN treatment to a level indistinguishable from ACC-deficient primary hepatocytes. This study shows that lipogenesis is dispensable for liver tumorigenesis in mice treated with DEN, and identifies an important role for ACC enzymes in redox regulation and cell survival.

Date: 2017
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DOI: 10.1038/ncomms14689

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